The goal of Core C is high-throughput production and analysis of AML genome sequence data. This includes data production, somatic and germline variant detection and validation, integration of various data types, and statistical inference of genetic alterations and their clinical implications. This will be achieved by employing cutting-edge technologies to generate high-quality DNA and RNA sequencing data and by using computational methods and tools to accurately analyze, identify, and categorize disease-causing and/or clinically relevant sequence variants and expression/methylation changes. The genomic data produced in Core C for cfe novo AML samples, AML relapse samples, MDS/AML families, and treatment-related AMLs will be comprehensive, including whole genome, exome, capture validation, and mRNA/sncRNA. Data from existing publically available catalogues of cancer-specific mutations, inherited variants related to genetic disease, and expression/methylation signatures will be used to further inform our analysis and clinical interpretation of identified genetic alterations in AML. Moreover, we will integrate genomic, epigenomic, and expression data from all projects at the pathway and network levels to understand how a diverse spectrum of genetic changes works together to drive AML initiation and progression. Finally, we will integrate genotypic and phenotypic data to facilitate the classification and discovery of genomic variants with clinical relevance and prognostic significance.